INSERM, U1016, Cochin Institute, CNRS UMR8104, University of Paris, 24 rue du Faubourg Saint-Jacques, Paris, France.
Inovarion, Paris, France.
Clin Epigenetics. 2023 Aug 2;15(1):121. doi: 10.1186/s13148-023-01534-5.
Adrenocortical carcinoma is rare and aggressive endocrine cancer of the adrenal gland. Within adrenocortical carcinoma, a recently described subtype characterized by a CpG island methylator phenotype (CIMP) has been associated with an especially poor prognosis. However, the drivers of CIMP remain unknown. Furthermore, the functional relation between CIMP and poor clinical outcomes of patients with adrenocortical carcinoma stays elusive.
Here, we show that CIMP in adrenocortical carcinoma is linked to the increased expression of DNA methyltransferases DNMT1 and DNMT3A driven by a gain of gene copy number and cell hyperproliferation. Importantly, we demonstrate that CIMP contributes to tumor aggressiveness by favoring tumor immune escape. This effect could be at least partially reversed by treatment with the demethylating agent 5-azacytidine.
In sum, our findings suggest that co-treatment with demethylating agents might enhance the efficacy of immunotherapy and could represent a novel therapeutic approach for patients with high CIMP adrenocortical carcinoma.
肾上腺皮质癌是一种罕见且侵袭性的肾上腺内分泌癌。在肾上腺皮质癌中，最近描述了一种具有 CpG 岛甲基化表型（CIMP）的亚型，与预后特别差有关。然而，CIMP 的驱动因素仍不清楚。此外，CIMP 与肾上腺皮质癌患者临床结局不良之间的功能关系仍不清楚。
在这里，我们表明，肾上腺皮质癌中的 CIMP 与 DNA 甲基转移酶 DNMT1 和 DNMT3A 的表达增加有关，这是由基因拷贝数增加和细胞过度增殖驱动的。重要的是，我们证明 CIMP 通过促进肿瘤免疫逃逸促进肿瘤侵袭性。这种作用至少可以部分通过使用去甲基化剂 5-氮杂胞苷来逆转。
总之，我们的研究结果表明，联合使用去甲基化剂可能会提高免疫疗法的疗效，并可能成为 CIMP 高的肾上腺皮质癌患者的一种新的治疗方法。
